THe injection of bovine pancreatic polypeptide reverses hyperphagia, obesity, hyperglycemia, and hyperinsulinemia in congenitally obese rodents. ALthough increased pancreatic concentrations of pancreatic polypeptide have been reported in ob/ob mice, conventional antisera raised against human or bovine pancreatic polypeptides do not crossreact specifically with rodent pancreatic polypeptide making interpretation of these results difficult. We have developed a specific radioimmunoassay for rodent pancreatic polypeptide which will be employed to compare tissue concentrations and molecular heterogeneity of pancreatic polypeptide in obese and lean mice. Cholecystokinin and bombesin are two other brain-gut peptides known to induce satiety in rodents. As both release pancreatic polypeptide it is possible that they exert their effects through release of pancreatic polypeptide. We will examine this hypothesis by comparing pancreatic polypeptide responses to exogenous cholecystokinin and bombesin in obese and lean mice and attempt to correlate these responses with the ability of each peptide to induce satiety and weight loss in these animals. Pancreatic polypeptide release is vagally dependent suggesting that if other satiety agents act through release of this peptide, their effects would be blocked by vagotomy. We will test this hypothesis by contrasting the ability of cholecystokinin and bombesin to reduce food intake in rats before and after abdominal vagotomy. Pancreatic polypeptide's role as a satiety factor in higher mammals will also be examined by measuring the effects of physiological doses of the peptide on amounts of food ingested by esophageal fistula dogs. Finally, release of pancreatic polypeptide and its molecular heterogeneity will be examined in obese patients with the Prader-Willi syndrome, a syndrome which bears similarities with the ob/ob mouse model of obesity. These studies will determine if pancreatic polypeptide is a satiety-inducing hormone in rodents and higher mammals. They will also determine if there is altered synthesis or release of the peptide in the ob/ob mouse and in patients with the Prader-Willie syndrome. Finally, a unifying theory of hormonal control of food intake may emerge, i.e., that other brain-gut peptides induce satiety through release of pancreatic polypeptide.